Reduced GABAergic Inhibition Explains Cortical Hyperexcitability in the Wobbler Mouse Model of ALS

Nieto-González, José Luis; Moser, Jakob; Lauritzen, Martin; Schmitt-John, Thomas; Jensen, Kimmo

doi:10.1093/cercor/bhq134

Cited by 71 publications

(59 citation statements)

References 43 publications

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“…Our findings of decreased NAA and increased mI are in accord with other published studies 37–40. Our findings of reduced GABA levels in the MC are supported by other indirect evidence of decreased cortical inhibition in ALS, including an ALS animal model, as well as human histochemical, positron emission tomography, and transcranial magnetic stimulation studies 41–44. For the DTI measures, we chose to focus on FA as this is the most commonly altered DTI measure in the ALS literature 16…”

Section: Discussionsupporting

confidence: 93%

Multimodal MRI as a diagnostic biomarker for amyotrophic lateral sclerosis

Foerster

Carlos

Dwamena

et al. 2014

Ann Clin Transl Neurol

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ObjectiveReliable biomarkers for amyotrophic lateral sclerosis (ALS) are needed, given the clinical heterogeneity of the disease. Here, we provide proof-of-concept for using multimodal magnetic resonance imaging (MRI) as a diagnostic biomarker for ALS. Specifically, we evaluated the added diagnostic utility of proton magnetic resonance spectroscopy (MRS) to diffusion tensor imaging (DTI).MethodsTwenty-nine patients with ALS and 30 age- and gender-matched healthy controls underwent brain MRI which used proton MRS including spectral editing techniques to measure γ-aminobutyric acid (GABA) and DTI to measure fractional anisotropy of the corticospinal tract. Data were analyzed using logistic regression, t-tests, and generalized linear models with leave-one-out analysis to generate and compare the resulting receiver operating characteristic (ROC) curves.ResultsThe diagnostic accuracy is significantly improved when the MRS data were combined with the DTI data as compared to the DTI data only (area under the ROC curves (AUC) = 0.93 vs. AUC = 0.81; P = 0.05). The combined MRS and DTI data resulted in sensitivity of 0.93, specificity of 0.85, positive likelihood ratio of 6.20, and negative likelihood ratio of 0.08 whereas the DTI data only resulted in sensitivity of 0.86, specificity of 0.70, positive likelihood ratio of 2.87, and negative likelihood ratio of 0.20.InterpretationCombining multiple advanced neuroimaging modalities significantly improves disease discrimination between ALS patients and healthy controls. These results provide an important step toward advancing a multimodal MRI approach along the diagnostic test development pathway for ALS.

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Section: Discussionsupporting

confidence: 93%

Multimodal MRI as a diagnostic biomarker for amyotrophic lateral sclerosis

Foerster

Carlos

Dwamena

et al. 2014

Ann Clin Transl Neurol

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“…Pathological studies demonstrate a particular vulnerability of parvalbumin‐positive interneurons [Maekawa et al, 2004; Nihei et al, 1993], later shown to contribute to reduced inhibitory GABA‐ergic tone in animal models [McGown et al, 2013; Nieto‐Gonzalez et al, 2011]. Neuroimaging studies across multiple modalities have supported the concept of reduced cortical inhibition.…”

Section: Discussionmentioning

confidence: 99%

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

Proudfoot

Rohenkohl

Quinn

et al. 2016

Human Brain Mapping

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Continuous rhythmic neuronal oscillations underpin local and regional cortical communication. The impact of the motor system neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) on the neuronal oscillations subserving movement might therefore serve as a sensitive marker of disease activity. Movement preparation and execution are consistently associated with modulations to neuronal oscillation beta (15–30 Hz) power. Cortical beta‐band oscillations were measured using magnetoencephalography (MEG) during preparation for, execution, and completion of a visually cued, lateralized motor task that included movement inhibition trials. Eleven “classical” ALS patients, 9 with the primary lateral sclerosis (PLS) phenotype, and 12 asymptomatic carriers of ALS‐associated gene mutations were compared with age‐similar healthy control groups. Augmented beta desynchronization was observed in both contra‐ and ipsilateral motor cortices of ALS patients during motor preparation. Movement execution coincided with excess beta desynchronization in asymptomatic mutation carriers. Movement completion was followed by a slowed rebound of beta power in all symptomatic patients, further reflected in delayed hemispheric lateralization for beta rebound in the PLS group. This may correspond to the particular involvement of interhemispheric fibers of the corpus callosum previously demonstrated in diffusion tensor imaging studies. We conclude that the ALS spectrum is characterized by intensified cortical beta desynchronization followed by delayed rebound, concordant with a broader concept of cortical hyperexcitability, possibly through loss of inhibitory interneuronal influences. MEG may potentially detect cortical dysfunction prior to the development of overt symptoms, and thus be able to contribute to the assessment of future neuroprotective strategies. Hum Brain Mapp 38:237–254, 2017. © 2016 Wiley Periodicals, Inc.

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“…Patients with ALS had significantly lower levels of GABA in the motor cortex than did healthy controls. Riluzole-naive patients with ALS had higher levels of glutamate-glutamine than did riluzole-treated patients with ALS or healthy controls 5 , 6 .…”

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confidence: 84%

Syphilis may be a confounding factor, not a causative agent, in syphilitic ALS

Tuk

2016

F1000Res

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Based upon a review of published clinical observations regarding syphilitic amyotrophic lateral sclerosis (ALS), I hypothesize that syphilis is actually a confounding factor, not a causative factor, in syphilitic ALS. Moreover, I propose that the successful treatment of ALS symptoms in patients with syphilitic ALS using penicillin G and hydrocortisone is an indirect consequence of the treatment regimen and is not due to the treatment of syphilis. Specifically, I propose that the observed effect is due to the various pharmacological activities of penicillin G ( e.g., a GABA receptor antagonist) and/or the multifaceted pharmacological activity of hydrocortisone. The notion that syphilis may be a confounding factor in syphilitic ALS is highly relevant, as it suggests that treating ALS patients with penicillin G and hydrocortisone—regardless of whether they present with syphilitic ALS or non-syphilitic ALS—may be effective at treating this rapidly progressive, highly devastating disease.

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Reduced GABAergic Inhibition Explains Cortical Hyperexcitability in the Wobbler Mouse Model of ALS

Cited by 71 publications

References 43 publications

Multimodal MRI as a diagnostic biomarker for amyotrophic lateral sclerosis

Multimodal MRI as a diagnostic biomarker for amyotrophic lateral sclerosis

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

Syphilis may be a confounding factor, not a causative agent, in syphilitic ALS

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